HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration
HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration
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DOI：
10.4161/auto.5050
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发表时间：
2007-11-01
期刊：
影响因子：
13.3
通讯作者：
Taylor, J. Paul
中科院分区：
文献类型：
--
作者：
Pandey, Udai Bhan;Batlevi, Yakup;Taylor, J. Paul
两个主要的细胞内分解代谢途径，泛素-蛋白酶体系统(UPS)和大自噬(自噬)，都被认为在神经退行性蛋白病中发挥作用。(1-2)我们利用果蝇神经退行性疾病的模型研究了UPS和自噬之间的关系。我们确定组蛋白去乙酰基酶6(HDAC6)是多聚谷氨酰胺诱导的神经变性的遗传修饰物，并确定其作用机制是自噬依赖的。(3)HDAC6抑制退行性疾病的能力已扩展到其他神经退行性疾病模型，包括本文提出的表达病理性Aβ片段的苍蝇模型，但不是退行性疾病表型的通用修饰物。重要的是，HDAC6还被发现以自噬依赖的方式抑制与蛋白酶体突变相关的退化，揭示了这两条降解途径之间的补偿关系。我们的发现表明，HDAC6促进了潜在有害蛋白底物的降解，对自噬的神经保护作用起到了至关重要的作用。
The two major intracellular catabolic pathways, the ubiquitin-proteasome system (UPS) and macroautophagy (autophagy), have each been implicated as playing roles in neurodegenerative proteinopathies.(1-2) We have investigated the relationship between the UPS and autophagy using Drosophila models of neurodegenerative diseases. We identified histone deacetylase 6 (HDAC6) as a genetic modifier of polyglutamine-induced neurodegeneration and determined that its mechanism of action is autophagy-dependent.(3) The ability of HDAC6 to suppress degeneration has been extended to additional neurodegenerative disease models, including a fly model expressing pathological A beta fragments, presented here, but is not a universal modifier of degenerative phenotypes. Importantly, HDAC6 was also found to suppress degeneration associated with proteasome mutations in an autophagy-dependent manner, revealing a compensatory relationship between these two degradation pathways. Our findings indicate that HDAC6 facilitates degradation of potentially noxious protein substrates, contributing vitally to the neuroprotective role of autophagy.